EP3735969A1 - Utilisation de canagliflozine dans la préparation d'un médicament anti-tumoral - Google Patents
Utilisation de canagliflozine dans la préparation d'un médicament anti-tumoral Download PDFInfo
- Publication number
- EP3735969A1 EP3735969A1 EP19912197.1A EP19912197A EP3735969A1 EP 3735969 A1 EP3735969 A1 EP 3735969A1 EP 19912197 A EP19912197 A EP 19912197A EP 3735969 A1 EP3735969 A1 EP 3735969A1
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- EP
- European Patent Office
- Prior art keywords
- canagliflozin
- cells
- drug
- preparation
- tumor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960001713 canagliflozin Drugs 0.000 title claims abstract description 40
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 title claims abstract description 40
- 229940079593 drug Drugs 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 title description 3
- 102000008096 B7-H1 Antigen Human genes 0.000 claims abstract description 37
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract description 37
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 20
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 3
- XTNGUQKDFGDXSJ-ZXGKGEBGSA-N Canagliflozin Chemical compound CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 XTNGUQKDFGDXSJ-ZXGKGEBGSA-N 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 239000003978 infusion fluid Substances 0.000 claims description 2
- 239000008176 lyophilized powder Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000007901 soft capsule Substances 0.000 claims description 2
- 210000001744 T-lymphocyte Anatomy 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 9
- 230000002147 killing effect Effects 0.000 abstract description 9
- 238000011160 research Methods 0.000 abstract description 5
- 238000009169 immunotherapy Methods 0.000 abstract description 4
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- 230000003828 downregulation Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 34
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 14
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 14
- 201000008968 osteosarcoma Diseases 0.000 description 11
- 230000014509 gene expression Effects 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 229940125644 antibody drug Drugs 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 102000008070 Interferon-gamma Human genes 0.000 description 4
- 108010074328 Interferon-gamma Proteins 0.000 description 4
- 102100020888 Sodium/glucose cotransporter 2 Human genes 0.000 description 4
- 101710103228 Sodium/glucose cotransporter 2 Proteins 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 4
- 229940044627 gamma-interferon Drugs 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 230000002222 downregulating effect Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 229940125645 monoclonal antibody drug Drugs 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000008844 regulatory mechanism Effects 0.000 description 2
- 229920001917 Ficoll Polymers 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 1
- 229940123573 Protein synthesis inhibitor Drugs 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000003235 crystal violet staining Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000007 protein synthesis inhibitor Substances 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to the pharmaceutical field, and particularly, relates to a use of canagliflozin in preparation of an antitumor drug.
- PD-1 and its ligand combine to form an immunosuppressive microenvironment, which plays a pivotal role in tumor immune escape.
- Several monoclonal antibody drugs that block the PD-1/PD-L1 combining have been successfully applied in the treatment of clinical hematological tumors and solid tumors, and some patients even reach a "clinically cured" status, providing a breakthrough progress in the field of tumor immunotherapy.
- clinical data indicate that PD-1/PD-L1 antibody drugs have significant clinical anti-tumor efficacy, PD-1/PD-L1 monoclonal antibody drugs still face huge challenges.
- the first challenge is to further enhance a response rate, which is low and is not greater than 20% in the treatment of most solid tumors. Some studies believed that a reason there of may be in that it is difficult for the macromolecular antibody drugs to effectively permeate into tumor tissue to reach all areas of the tumor in a sufficient amount.
- the second challenge is to further reduce adverse reactions.
- immune-related adverse events are discrete toxicity caused by non-specific activation of the immune system and may affect almost all organ systems.
- small molecular drugs have advantages such as good permeability inorgans or tumors, light stimulation to the immune system, and capability of oral administration. Therefore, an important approach to overcome the defects of antibody drugs is to develop small molecular drugs targeting PD-1/PD-L1, which is also a focus of research in this field.
- canagliflozin is a drug for the clinical treatment of type 2 diabetes mellitus, and its pharmacological mechanism is to inhibit a reabsorption of glucose by inhibiting the activity of sodium-glucose cotransporter 2 (SGLT2) and to promote glucose excretion, so as to achieve the effect of lowering blood sugar level.
- SGLT2 sodium-glucose cotransporter 2
- Canagliflozin is widely used in the treatment of diabetes mellitus because it has a significant hypoglycemic efficacy in hyperglycemic patients and almost has no influence on the normal blood sugar level, and diabetic patients have low risk of hypoglycemia and few adverse reactions when using this type of drugs to lower blood sugar level.
- a purpose of the present invention is to provide a use of canagliflozin in preparation of an antitumor drug, especially in preparation of a drug for treating solid tumors induced by an increased protein level of PD-L1 in tumor cells.
- a chemical name of canagliflozin is (1S)-1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol, with a molecular formula of C18H42O6Si4 and a molecular weight of 466.86448.
- canagliflozin (20 ⁇ M) significantly lowered the expressions of immune checkpoint protein PD-L1 and cell surface PD-L1 in non-small cell lung cancer cells and osteosarcoma cells.
- canagliflozin can effectively enhance a killing effect of T cells on tumor cells, which was similar to that of a positive control PD-L1 antibody drug.
- the drug is prepared with canagliflozin and pharmaceutically acceptable excipients, and is in a formulation of gel, soft capsule, oral preparation, injection solution, lyophilized powder for injection, or infusion solution.
- the drug is administrated once a day.
- Canagliflozin is an activity inhibitor of sodium-glucose cotransporter 2 (SGLT2), and is mainly used for the current clinical treatment of type 2 diabetes mellitus.
- the present invention has proven by in-vitro assays that canagliflozin has a significant down-regulation effect on the immune checkpoint protein PD-L1 in various tumor cells, and can effectively enhance the killing effect of T cells on tumor cells in the co-incubation model of T cells and tumor cells, thereby broadening a clinical application scope of the chemical drug canagliflozin in tumor immunotherapy.
- the present invention not only provides possibilities of applying canagliflozin in the clinical tumor treatments, but also provides new approaches and potential targets for the development of small molecular drugs based on PD-L1.
- canagliflozin used for clinical treatment of type 2 diabetes mellitus, can significantly lower the PD-L1 protein level in various tumor cells and restore the killing effect of T cells on tumor cells.
- small molecular inhibitors which achieve the antitumor efficacy by intervening in the protein expression regulation mechanism of PD-L1.
- the present invention uses the existing small molecular inhibitor for tumor immunotherapy, and provides new medical uses for canagliflozin.
- non-small cell lung cancer H1299 cells and osteosarcoma MG63 cells were selected and respectively inoculated in 6-well plates (1.0 ⁇ 10 6 cells/well), and incubated overnight in incubator at 37°C with 5% CO 2 .
- each plate was added with canagliflozin (20 ⁇ M) and ⁇ -interferon (IFN ⁇ , 10ng/mL), and after 24 hours, the cells were collected and lysed to extract the proteins.
- the expression of PD-L1 in the cells were detected by Western blotting.
- the inhibitory effects of canagliflozin on the PD-L1 protein in the non-small cell lung cancer H1299 cells and the osteosarcoma MG63 cells are illustrated in FIG. 1 , showing that canagliflozin significantly inhibited the PD-L1 total protein expression in the tumor cells.
- the specific inhibitory effects of canagliflozin on the PD-L1 protein in the non-small cell lung cancer H1299 cells and the osteosarcoma MG63 cells are illustrated in FIG. 2 , showing that canagliflozin significantly inhibited the PD-L1 protein expression on the tumor cell surfaces.
- the non-small cell lung cancer H1299 cells were inoculated in 6-well plates (1.0 ⁇ 10 6 cells/well), and incubated overnight in incubator at 37 °C with 5% CO 2 . On the next day, the plates were first added with ⁇ -interferon (IFN ⁇ , 10ng/mL), and after 24 hours, a protein synthesis inhibitor cycloheximide (CHX, 10 ⁇ g/mL) or a co-administration group of CHX (10 ⁇ g/mL) + canagliflozin (20 ⁇ M) was administrated simultaneously for these plates.
- IFN ⁇ ⁇ -interferon
- CHX protein synthesis inhibitor cycloheximide
- canagliflozin 20 ⁇ M
- the cells were collected to detect the change of the protein level of PD-L1 in the cells by Western blotting, and a gray-scale analysis was performed to plot a curve for investigating the protein stability. As shown in FIG. 3 , canagliflozin significantly promoted the degradation of the PD-L1 protein and shortened a half-life of the PD-L1 protein.
- PBMC cells were isolated from human blood samples using Ficoll separation solution, and then stimulated with CD3 and CD28 for 3 days to activate T cells in PBMC, and in the meantime, interleukin-2 (IL-2, 50U/uL) was administrated to maintain the growth of T cells.
- the activated T cells were co-incubated with the tumor cells that had been treated with canagliflozin (20 ⁇ M) and ⁇ -interferon (IFN ⁇ , 10ng/mL) for 24 hours.
- canagliflozin canagliflozin (20 ⁇ M) and ⁇ -interferon (IFN ⁇ , 10ng/mL) for 24 hours.
- IFN ⁇ ⁇ -interferon
- a PD-L1 antibody drug was used as a positive control.
- the killing effect of T cells on tumor cells was investigated, and a crystal violet staining method was employed to investigate the killing effect of T cells on tumor cells. The specific results are shown in FIG. 4 , showing that canagliflozin
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- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910391746.2A CN110038009B (zh) | 2019-05-13 | 2019-05-13 | 卡格列净在制备抗肿瘤药物中的应用 |
| PCT/CN2019/115242 WO2020168741A1 (fr) | 2019-05-13 | 2019-11-04 | Utilisation de canagliflozine dans la préparation d'un médicament anti-tumoral |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP3735969A1 true EP3735969A1 (fr) | 2020-11-11 |
| EP3735969A4 EP3735969A4 (fr) | 2021-05-19 |
Family
ID=67281636
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19912197.1A Pending EP3735969A4 (fr) | 2019-05-13 | 2019-11-04 | Utilisation de canagliflozine dans la préparation d'un médicament anti-tumoral |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US11534448B2 (fr) |
| EP (1) | EP3735969A4 (fr) |
| CN (1) | CN110038009B (fr) |
| WO (1) | WO2020168741A1 (fr) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112439067B (zh) * | 2019-09-03 | 2023-03-17 | 清华大学深圳研究生院 | Sglt2抑制剂在制备改善抗肿瘤药物敏感性的产品中的应用 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130281386A1 (en) | 2012-04-19 | 2013-10-24 | Eleison Pharmaceuticals LLC | Glufosfamide Combination Therapies for Cancer |
| WO2016134486A1 (fr) | 2015-02-27 | 2016-09-01 | Steinberg Gregory | Utilisation de canagliflozine et de ses dérivés dans le traitement du cancer |
| US20170071970A1 (en) * | 2015-09-15 | 2017-03-16 | Janssen Pharmaceutica Nv | Co-therapy comprising canagliflozin and phentermine for the treatment of obesity and obesity related disorders |
| EP3490543A4 (fr) | 2016-08-01 | 2020-04-01 | IC-Medtech Corp. | Acide ascorbique, composé de quinone et inhibiteur de co-transporteur de glucose de sodium pour le traitement du cancer. |
-
2019
- 2019-05-13 CN CN201910391746.2A patent/CN110038009B/zh active Active
- 2019-11-04 EP EP19912197.1A patent/EP3735969A4/fr active Pending
- 2019-11-04 US US16/976,765 patent/US11534448B2/en active Active
- 2019-11-04 WO PCT/CN2019/115242 patent/WO2020168741A1/fr unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020168741A1 (fr) | 2020-08-27 |
| EP3735969A4 (fr) | 2021-05-19 |
| US20220062316A1 (en) | 2022-03-03 |
| CN110038009B (zh) | 2021-01-08 |
| US11534448B2 (en) | 2022-12-27 |
| CN110038009A (zh) | 2019-07-23 |
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